Method and apparatus for the use of [11c] carbon monoxide in labeling synthesis by photo-intiated carbonylation

ABSTRACT

Methods and reagents for photo-initiated carbonylation with carbon-isotope labeled carbon monoxide using amines and alkyl/aryl iodides are provided. The resultant carbon-isotope labeled amides are useful as radiopharmaceuticals, especially for use in Positron Emission Tomography (PET). Associated kits for PET studies are also provided.

FIELD OF THE INVENTION

The present invention relates to a method and an apparatus for the useof carbon-isotope monoxide in labeling synthesis. More specifically, theinvention relates to a method and apparatus for producing an [¹¹C]carbonmonoxide enriched gas mixture from an initial [¹¹C]carbon dioxide gasmixture, and using the produced gas mixture in labeling synthesis byphoto-initiated carbonylation. Radiolabeled amides are provided usingamines and alkyl iodides as precursors.

BACKGROUND OF THE INVENTION

Tracers labeled with short-lived positron emitting radionuclides (e.g.¹¹C, t_(1/2)=20.3 min) are frequently used in various non-invasive invivo studies in combination with positron emission tomography (PET).Because of the radioactivity, the short half-lives and the submicromolaramounts of the labeled substances, extraordinary synthetic proceduresare required for the production of these tracers. An important part ofthe elaboration of these procedures is development and handling of new¹¹C-labelled precursors. This is important not only for labeling newtypes of compounds, but also for increasing the possibility of labelinga given compound in different positions.

During the last two decades carbonylation chemistry using carbonmonoxide has developed significantly. The recent development of methodssuch as palladium-catalysed carbonylative coupling reactions hasprovided a mild and efficient tool for the transformation of carbonmonoxide into different carbonyl compounds.

Carbonylation reactions using [¹¹C]carbon monoxide has a primary valuefor PET-tracer synthesis since biologically active substances oftencontain carbonyl groups or functionalities that can be derived from acarbonyl group. The syntheses are tolerant to most functional groups,which means that complex building blocks can be assembled in thecarbonylation step to yield the target compound. This is particularlyvaluable in PET-tracer synthesis where the unlabelled substrates shouldbe combined with the labeled precursor as late as possible in thereaction sequence, in order to decrease synthesis-time and thus optimizethe uncorrected radiochemical yield.

When compounds are labeled with ¹¹C, it is usually important to maximizespecific radioactivity. In order to achieve this, the isotopic dilutionand the synthesis time must be minimized. Isotopic dilution fromatmospheric carbon dioxide may be substantial when [¹¹C]carbon dioxideis used in a labeling reaction. Due to the low reactivity andatmospheric concentration of carbon monoxide (0.1 ppm vs. 3.4×10⁴ ppmfor CO₂), this problem is reduced with reactions using [¹¹C]carbonmonoxide.

The synthesis of [¹¹C]carbon monoxide from [¹¹C]carbon dioxide using aheated column containing reducing agents such as zinc, charcoal ormolybdenum has been described previously in several publications.Although [¹¹C]carbon monoxide was one of the first ¹¹C-labelledcompounds to be applied in tracer experiments in human, it has untilrecently not found any practical use in the production of PET-tracers.One reason for this is the low solubility and relative slow reactionrate of [¹¹C]carbon monoxide which causes low trapping efficiency inreaction media. The general procedure using precursors such as[¹¹C]methyl iodide, [¹¹C]hydrogen cyanide or [¹¹C]carbon dioxide is totransfer the radioactivity in a gas-phase, and trap the radioactivity byleading the gas stream through a reaction medium. Until recently thishas been the only accessible procedure to handle [¹¹C]carbon monoxide inlabeling synthesis. With this approach, the main part of the labelingsyntheses with [¹¹C]carbon monoxide can be expected to give a very lowyield or fail completely.

There are only a few examples of practically valuable ¹¹C-labellingsyntheses using high pressure techniques (>300 bar). In principal, highpressures can be utilized for increasing reaction rates and minimizingthe amounts of reagents. One problem with this approach is how toconfine the labeled precursor in a small high-pressure reactor. Anotherproblem is the construction of the reactor. If a common column type ofreactor is used (i.e. a cylinder with tubing attached to each end), thegas-phase will actually become efficiently excluded from the liquidphase at pressurization. The reason is that the gas-phase, in contractedform, will escape into the attached tubing and away from the bulk amountof the liquid reagent.

The cold-trap technique is widely used in the handling of ¹¹C-labelledprecursors, particularly in the case of [¹¹C]carbon dioxide. Theprocedure has, however, only been performed in one single step and thelabeled compound was always released in a continuous gas-streamsimultaneous with the heating of the cold-trap. Furthermore, the volumeof the material used to trap the labeled compound has been relativelarge in relation to the system to which the labeled compound has beentransferred. Thus, the option of using this technique for radicalconcentration of the labeled compound and miniaturization of synthesissystems has not been explored. This is especially noteworthy in view ofthe fact that the amount of a “C-labelled compound usually is in therange 20-60 mmol.

Recent technical development for the production and use of [¹¹C] carbonmonoxide has made this compound useful in labeling synthesis. WO02/102711 describes a system and a method for the production and use ofa carbon-isotope monoxide enriched gas-mixture from an initialcarbon-isotope dioxide gas mixture. [¹¹C] carbon monoxide may beobtained in high radiochemical yield from cyclotron produced [¹¹C]carbon dioxide and can be used to yield target compounds with highspecific radioactivity. This reactor overcomes the difficulties listedabove and is useful in synthesis of ¹¹C-labelled compounds using [¹¹C]carbon monoxide in palladium or selenium mediated reaction. With suchmethod, a broad array of carbonyl compounds can be labeled (Kilhlberg,T.; Langstrom, B. J., Org. Chem. 1999, 9201-9205). The use of transitionmetal mediated reactions is, however, restricted by problems related tothe competing β-hydride elimination reaction, which excludes or at leastseverely restricts utilization of organic electrophiles having hydrogenin β-position. Therefore, there is a need for a system and method inorder to circumvent the problem with β-hydride elimination to complementthe palladium mediated reactions and provide target structures tofurther increase the utility of [¹¹C] carbon monoxide in preparinguseful PET tracers.

Discussion or citation of a reference herein shall not be construed asan admission that such reference is prior art to the present invention.

SUMMARY OF THE INVENTION

The present invention provides a method for labeling synthesis,comprising:

(a) providing a UV reactor assembly comprising a high pressure reactionchamber, a UV lamp and a concave mirror, wherein the high pressurereaction chamber having a window facing the concave mirror, a liquidinlet and a gas inlet in a bottom surface thereof,

(b) providing a reagent volume to be labeled,

(c) introducing a carbon-isotope monoxide enriched gas-mixture into thereaction chamber of the UV reactor assembly via the gas inlet,

(d) introducing at high-pressure said reagent into the reaction chambervia the liquid inlet,

(e) turning on the UV lamp and waiting a predetermined time while thelabeling synthesis occur, and

(f) removing the labeled product from the reaction chamber.

The present invention also provides a system for labeling synthesis,comprising: a UV reactor assembly comprising a high pressure reactionchamber, a UV lamp and a concave mirror, wherein the high pressurereaction chamber having a window facing the concave mirror, a liquidinlet and a gas inlet in a bottom surface thereof, wherein the concavemirror can focus the UV light from the UV lamp, and the focused lightbeam enters the window of the reaction chamber.

The present invention further provides a method for the synthesis oflabeled amides using photo-initiated carbonylation with [¹¹C] carbonmonoxide using amines and alkyl or aryl iodides.

In yet another embodiment, the invention also provides [“C]-labeledamides. In still another embodiment, the invention provides kits for useas PET tracers comprising [¹¹C]-labeled amides.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a flow chart over the method according to the invention

FIG. 2 is a schematic view of a carbon-isotope monoxide production andlabeling-system according to the invention.

FIG. 3 shows the main parts of the UV reactor assembly.

FIG. 4 is the schematic diagram of the optical scheme of the UV reactorassembly.

FIG. 5 is the cross-sectional view of the reaction chamber.

FIG. 6 shows reaction chamber and its cooling jacket.

FIGS. 7 a and 7 b show alternative embodiments of a reaction chamberaccording to the invention.

DETAILED DESCRIPTION OF THE INVENTION

The object of the invention is to provide a method and a system forproduction of and use of carbon-isotope monoxide in labeling synthesisthat overcomes the drawbacks of the prior art devices. This is achievedby the method and system claimed in the invention.

One advantage with such a method and system is that nearly quantitativeconversion of carbon-isotope monoxide into labeled products can beaccomplished.

There are several other advantages with the present method and system.The high-pressure technique makes it possible to use low boilingsolvents such as diethyl ether at high temperatures (e.g. 200° C.). Theuse of a closed system consisting of materials that prevents gasdiffusion, increases the stability of sensitive compounds and could beadvantageous also with respect to Good Manufacturing Practice (GMP).

Still other advantages are achieved in that the resulting labeledcompound is highly concentrated, and that the miniaturization of thesynthesis system facilitates automation, rapid synthesis andpurification, and optimization of specific radioactivity throughminimization of isotopic dilution.

Most important is the opening of completely new synthesis possibilities,as exemplified by the present invention.

Embodiments of the invention will now be described with reference to thefigures.

The term carbon-isotope that is used throughout this applicationpreferably refers to ¹¹C, but it should be understood that ¹¹C may besubstituted by other carbon-isotopes, such as ¹³C and ¹⁴C, if desired.

FIG. 1 shows a flow chart over the method according to the invention,which firstly comprises production of a carbon-isotope monoxide enrichedgas-mixture and secondly a labeling synthesis procedure. More in detailthe production part of the method comprises the steps of:

-   -   Providing carbon-isotope dioxide in a suitable carrier gas of a        type that will be described in detail below.    -   Converting carbon-isotope dioxide to carbon-isotope monoxide by        introducing said gas mixture in a reactor device which will be        described in detail below.    -   Removing traces of carbon-isotope dioxide by flooding the        converted gas-mixture through a carbon dioxide removal device        wherein carbon-isotope dioxide is trapped but not carbon-isotope        monoxide nor the carrier gas, The carbon dioxide removal device        will be described in detail below.    -   Trapping carbon-isotope monoxide in a carbon monoxide trapping        device, wherein carbon-isotope monoxide is trapped but not said        carrier gas. The carbon monoxide trapping device will be        described in detail below.    -   Releasing said trapped carbon-isotope monoxide from said        trapping device, whereby a volume of carbon-isotope monoxide        enriched gas-mixture is achieved.

The production step may further comprise a step of changing carrier gasfor the initial carbon-isotope dioxide gas mixture if the initialcarbon-isotope dioxide gas mixture is comprised of carbon-isotopedioxide and a first carrier gas not suitable as carrier gas for carbonmonoxide due to similar molecular properties or the like, such asnitrogen. More in detail the step of providing carbon-isotope dioxide ina suitable second carrier gas such as He, Ar, comprises the steps of:

-   -   Flooding the initial carbon-isotope dioxide gas mixture through        a carbon dioxide trapping device, wherein carbon-isotope dioxide        is trapped but not said first carrier gas. The carbon dioxide        trapping device will be described in detail below.    -   Flushing said carbon dioxide trapping device with said suitable        second carrier gas to remove the remainders of said first        carrier gas.    -   Releasing said trapped carbon-isotope dioxide in said suitable        second carrier gas.

The labeling synthesis step that may follow the production step utilizesthe produced carbon-isotope dioxide enriched gas-mixture as labelingreactant. More in detail the step of labeling synthesis comprises thesteps of:

-   -   Providing a UV reactor assembly comprising a UV lamp, a concave        mirror and a high pressure reaction chamber having a liquid        reagent inlet and a labeling reactant inlet in a bottom surface        thereof. The UV reactor assembly and the reaction chamber will        be described in detail below.    -   Providing a liquid reagent volume that is to be labeled.        Suitable samples are discussed above.    -   Introducing the carbon-isotope monoxide enriched gas-mixture        into the reaction chamber via the labeling reactant inlet.    -   Introducing, at high pressure, said liquid reagent into the        reaction chamber via the liquid reagent inlet.    -   Turning on the UV lamp and waiting a predetermined time while        the labeling synthesis occur.    -   Removing the solution of labeled product from the reaction        chamber.

The step of waiting a predetermined time may further comprise adjustingthe temperature of the reaction chamber such that the labeling synthesisis enhanced.

FIG. 2 schematically shows a [¹¹C]carbon dioxide production andlabeling-system according to the present invention. The system iscomprised of three main blocks, each handling one of the three mainsteps of the method of production and labeling:

-   -   Block A is used to perform a change of carrier gas for an        initial carbon-isotope dioxide gas mixture, if the initial        carbon-isotope dioxide gas mixture is comprised of        carbon-isotope dioxide and a first carrier gas not suitable as        carrier gas for carbon monoxide.    -   Block B is used to perform the conversion from carbon-isotope        dioxide to carbon-isotope monoxide, and purify and concentrate        the converted carbon-isotope monoxide gas mixture.    -   Block C is used to perform the carbon-isotope monoxide labeling        synthesis.

Block A is normally needed due to the fact that carbon-isotope dioxideusually is produced using the 14N(p,α)¹¹C reaction in a target gascontaining nitrogen and 0.1% oxygen, bombarded with 17 MeV protons,whereby the initial carbon-isotope dioxide gas mixture comprisesnitrogen as carrier gas. However, compared with carbon monoxide,nitrogen show certain similarities in molecular properties that makes itdifficult to separate them from each other, e.g. in a trapping device orthe like, whereby it is difficult to increase the concentration ofcarbon-isotope monoxide in such a gas mixture. Suitable carrier gasesmay instead be helium, argon or the like. Block A can also used tochange the pressure of the carrier gas (e.g. from 1 to 4 bar), in casethe external system does not tolerate the gas pressure needed in block Band C. In an alternative embodiment the initial carbon-isotope dioxidegas mixture is comprised of carbon-isotope dioxide and a first carriergas that is well suited as carrier gas for carbon monoxide, whereby theblock A may be simplified or even excluded.

According to a preferred embodiment (FIG. 2), block A is comprised of afirst valve V1, a carbon dioxide trapping device 8, and a second valveV2. The first valve V1 has a carbon dioxide inlet 10 connected to asource of initial carbon-isotope dioxide gas mixture 12, a carrier gasinlet 14 connected to a source of suitable carrier gas 16, such ashelium, argon and the like. The first valve V1 further has a firstoutlet 18 connected to a first inlet 20 of the second valve V2, and asecond outlet 22 connected to the carbon dioxide trapping device 8. Thevalve V1 may be operated in two modes A, B, in mode A the carbon dioxideinlet 10 is connected to the first outlet 18 and the carrier gas inlet14 is connected to the second outlet 22, and in mode B the carbondioxide inlet 10 is connected to the second outlet 22 and the carriergas inlet 14 is connected to the first outlet 18.

In addition to the first inlet 20, the second valve V2 has a secondinlet 24 connected to the carbon dioxide trapping device 8. The secondvalve V2 further has a waste outlet 26, and a product outlet 28connected to a product inlet 30 of block B. The valve V2 may be operatedin two modes A, B, in mode A the first inlet 20 is connected to thewaste outlet 26 and the second inlet 24 is connected to the productoutlet 28, and in mode B the first inlet 20 is connected to the productoutlet 28 and the second inlet 24 is connected to the waste outlet 26.

The carbon dioxide trapping device 8 is a device wherein carbon dioxideis trapped but not said first carrier gas, which trapped carbon dioxidethereafter may be released in a controlled manner. This may preferablybe achieved by using a cold trap, such as a column containing a materialwhich in a cold state, (e.g. −196° C. as in liquid nitrogen or −186° C.as in liquid argon) selectively trap carbon dioxide and in a warm state(e.g. +50° C.) releases the trapped carbon dioxide. (In this text theexpression “cold trap” is not restricted to the use of cryogenics. Thus,materials that traps the topical compound at room temperature andrelease it at a higher temperature are included). One suitable materialis porapac Q®. The trapping behavior of a porapac-column is related todipole-dipole interactions or possibly Van der Waal interactions. Thesaid column 8 is preferably formed such that the volume of the trappingmaterial is to be large enough to efficiently trap (>95%) thecarbon-isotope dioxide, and small enough not to prolong the transfer oftrapped carbon dioxide to block B. In the case of porapac Q® and a flowof 100 ml nitrogen/min, the volume should be 50-150 μl. The cooling andheating of the carbon dioxide trapping device 8 may further be arrangedsuch that it is performed as an automated process, e.g. by automaticallylowering the column into liquid nitrogen and moving it from there into aheating arrangement.

According to the preferred embodiment of FIG. 2 block B is comprised ofa reactor device 32 in which carbon-isotope dioxide is converted tocarbon-isotope monoxide, a carbon dioxide removal device 34, acheck-valve 36, and a carbon monoxide trapping device 38, which all areconnected in a line.

In the preferred embodiment the reactor device 32 is a reactor furnacecomprising a material that when heated to the right temperature intervalconverts carbon-isotope dioxide to carbon-isotope monoxide. A broadrange of different materials with the ability to convert carbon dioxideinto carbon monoxide may be used, e.g. zinc or molybdenum or any otherelement or compound with similar reductive properties. If the reactordevice 32 is a zinc furnace it should be heated to 400° C., and it isimportant that the temperature is regulated with high precision. Themelting point of zinc is 420° C. and the zinc-furnace quickly loses itability to transform carbon dioxide into carbon monoxide when thetemperature reaches over 410° C., probably due to changed surfaceproperties. The material should be efficient in relation to its amountto ensure that a small amount can be used, which will minimize the timeneeded to transfer radioactivity from the carbon dioxide trapping device8 to the subsequent carbon monoxide trapping device 38. The amount ofmaterial in the furnace should be large enough to ensure a practicallife-time for the furnace (at least several days). In the case of zincgranulates, the volume should be 100-1000 μl.

The carbon dioxide removal device 34 is used to remove traces ofcarbon-isotope dioxide from the gas mixture exiting the reactor device32. In the carbon dioxide removal device 34, carbon-isotope dioxide istrapped but not carbon-isotope monoxide nor the carrier gas. The carbondioxide removal device 34 may be comprised of a column containingascarite® (i.e. sodium hydroxide on silica). Carbon-isotope dioxide thathas not reacted in the reactor device 32 is trapped in this column (itreacts with sodium hydroxide and turns into sodium carbonate), whilecarbon-isotope monoxide passes through. The radioactivity in the carbondioxide removal device 34 is monitored as a high value indicates thatthe reactor device 32 is not functioning properly.

Like the carbon dioxide trapping device 8, the carbon monoxide trappingdevice 38, has a trapping and a releasing state. In the trapping statecarbon-isotope monoxide is selectively trapped but not said carrier gas,and in the releasing state said trapped carbon-isotope monoxide isreleased in a controlled manner. This may preferably be achieved byusing a cold trap, such as a column containing silica which selectivelytrap carbon monoxide in a cold state below −100° C., e.g. −196° C. as inliquid nitrogen or −186° C. as in liquid argon, and releases the trappedcarbon monoxide in a warm state (e.g. +50° C.). Like the porapac-column,the trapping behavior of the silica-column is related to dipole-dipoleinteractions or possibly Van der Waal interactions. The ability of thesilica-column to trap carbon-isotope monoxide is reduced if the helium,carrying the radioactivity, contains nitrogen. A rationale is that sincethe physical properties of nitrogen are similar to carbon monoxide,nitrogen competes with carbon monoxide for the trapping sites on thesilica.

According to the preferred embodiment of FIG. 2, block C is comprised ofa first and a second reaction chamber valve V3 and V4, a reagent valveV5, an injection loop 70 and a solvent valve V6, and the UV reactorassembly 51 which comprises a UV lamp 91, a concave mirror 92 and areaction chamber 50.

The first reaction chamber valve V3 has a gas mixture inlet 40 connectedto the carbon monoxide trapping device 38, a stop position 42, acollection outlet 44, a waste outlet 46, and a reaction chamberconnection port 48 connected to a gas inlet 52 of the reaction chamber50. The first reaction chamber valve V3 has four modes of operation A toD. The reaction chamber connection port 48 is: in mode A connected tothe gas mixture inlet 40, in mode B connected to the stop position 42,in mode C connected to the collection outlet 44, and in mode D connectedto the waste outlet 46.

FIG. 3 is a diagram of UV reactor assembly 51. It comprises of a UV lamp91, a concave mirror 92, a reaction chamber 50. In a preferredembodiment, it also includes a bench 93 and protective housing 94, sothat all parts located inside of the protective housing and mounted onthe bench. In the most preferred embodiment, it further comprises amotor 95, a magnet stirrer 96, a magnet stirring bar 97 and athermocouple 98 (see FIG. 5).

In a preferred embodiment, all parts are mounted on a bench. They areshielded with a thin protective housing outside for protection againstUV radiation. Compressed air is supplied through inlet attached to thetop face of the housing to ventilate the device and to provide normaloperation conditions for the UV lamp.

The optical scheme is illustrated in FIG. 4. A spherical concave mirroris used to collect the output of the arc and direct it onto the reactorcavity. The light source and reactor are displaced from the optical axisof the mirror so that the Iw lamp does not block the light collected bythe mirror. This also prevents the bulb from overheating. Distancebetween the reactor and the lamp is kept at minimum to ensure smallestarc image.

The reaction chamber 50 (micro-autoclave) has a gas inlet 52 and aliquid inlet 54, which are arranged such that they terminate at thebottom surface of the chamber. Gas inlet 52 may also be used as productoutlet after the labeling is finished. During operation thecarbon-isotope monoxide enriched gas mixture is introduced into thereaction chamber 50 through the gas inlet 52, where after the liquidreagent at high pressure enters the reaction chamber 50 through theliquid inlet 54. FIGS. 3 a and 3 b shows schematic views of twopreferred reaction chambers 50 in cross section. FIG. 7 a is acylindrical chamber which is fairly easy to produce, whereas thespherical chamber of FIG. 7 b is the most preferred embodiment, as thesurface area to volume-ratio of the chamber is further minimized. Aminimal surface area to volume-ratio optimizes the recovery of labeledproduct and minimizes possible reactions with the surface material. Dueto the “diving-bell construction” of the reaction chamber 50, both thegas inlet 52 and the liquid inlet 54 becomes liquid-filled and thereaction chamber 50 is filled from the bottom upwards. The gas-volumecontaining the carbon-isotope monoxide is thus trapped and givenefficient contact with the reaction mixture. Since the final pressure ofthe liquid is approximately 80 times higher than the original gaspressure, the final gas volume will be less than 2% of the liquid volumeaccording to the general gas-law. Thus, a pseudo one-phase system willresult. In the instant application, the term “pseudo one-phase system”means a closed volume with a small surface area to volume-ratiocontaining >96% liquid and <4% gas at pressures exceeding 200 bar. Inmost syntheses the transfer of carbon monoxide from the gas-phase to theliquid phase will probably not be the rate limiting step. After thelabeling is finished the labeled volume is nearly quantitativelytransferred from the reaction chamber by the internal pressure via thegas inlet/product outlet 52 and the first reaction chamber valve V3 inposition C.

In a specific embodiment, FIG. 5 shows a reaction chamber made fromstainless steel (Valco™) column end fitting. It is equipped withsapphire window, which is a hard material transparent to shortwavelength UV radiation. The window is pressed between two Teflonwashers inside the drilled column end fitting to make the reactor tightat high pressures. Temperature measurement can be accomplished with thethermocouple 98 attached by solder drop to the outer side of thereactor. The magnet stirrer drives small Teflon coated magnet placeinside the reaction chamber. The magnetic stirrer can be attached to theside of the reaction chamber in the assembly. Distance between themagnet stirrer and the reactor should be minimal.

FIG. 6 illustrates a device used to remove excessive heat produced bythe light source and keep the reaction chamber at constant temperature.Copper tube can be placed into the short piece of copper tube of largerdiameter filled up with lead alloy. Hexagonal hole can be made to fitthe reaction chamber nut tightly. To increase heat transfer betweenreactor and the thermostat, thermoconductive silicon grease can be used.The thermostat can then be connected to standalone water bath thermostatwith rubber tubes.

Referring back to FIG. 2, the second reaction chamber valve V4 has areaction chamber connection port 56, a waste outlet 58, and a reagentinlet 60. The second reaction chamber valve V4 has two modes ofoperation A and B. The reaction chamber connection port 56 is: in mode Aconnected to the waste outlet 58, and in mode B it is connected to thereagent inlet 60.

The reagent valve V5, has a reagent outlet 62 connected to the reagentinlet 60 of the second reaction chamber valve V4, an injection loopinlet 64 and outlet 66 between which the injection loop 70 is connected,a waste outlet 68, a reagent inlet 71 connected to a reagent source, anda solvent inlet 72. The reagent valve V5, has two modes of operation Aand B. In mode A the reagent inlet 71 is connected to the injection loopinlet 64, and the injection loop outlet 66 is connected to the wasteoutlet 68, whereby a reagent may be fed into the injection loop 70. Inmode B the solvent inlet 72 is connected to the injection loop inlet 64,and the injection loop outlet 66 is connected to the reagent outlet 62,whereby reagent stored in the injection loop 70 may be forced via thesecond reaction chamber valve V4 into the reaction chamber 50 if a highpressure is applied on the solvent inlet 72.

The solvent valve V6, has a solvent outlet 74 connected to the solventinlet 72 of the reagent valve V5, a stop position 76, a waste outlet 78,and a solvent inlet 80 connected to a solvent supplying HPLC-pump (HighPerformance Liquid Chromatography) or any liquid-pump capable of pumpingorganic solvents at 0-10 ml/min at pressures up to 400 bar (not shown).The solvent valve V6, has two modes of operation A and B. In mode A thesolvent outlet 74 is connected to the stop position 76, and the solventinlet 80 is connected to the waste outlet 78. In mode B the solventoutlet 74 is connected to the solvent inlet 80, whereby solvent may bepumped into the system at high pressure by the HPLC-pump.

Except for the small volume of silica in the carbon monoxide trappingdevise 38, an important difference in comparison to the carbon dioxidetrapping device 8, as well as to all related prior art, is the procedureused for releasing the carbon monoxide. After the trapping of carbonmonoxide on carbon monoxide trapping devise 8, valve V3 is changed fromposition A to B to stop the flow from the carbon monoxide trappingdevise 38 and increase the gas-pressure on the carbon monoxide trappingdevise 38 to the set feeding gas pressure (3-5 bar). The carbon monoxidetrapping devise 38 is then heated to release the carbon monoxide fromthe silica surface while not significantly expanding the volume ofcarbon monoxide in the carrier gas. Valve V4 is changed from position Ato B and valve V3 is then changed from position B to A. At this instancethe carbon monoxide is rapidly and almost quantitatively transferred ina well-defined micro-plug into the reaction chamber 50. Micro-plug isdefined as a gas volume less than 10% of the volume of the reactionchamber 50, containing the topical substance (e.g. 1-20 μL). This uniquemethod for efficient mass-transfer to a small reaction chamber 50,having a closed outlet, has the following prerequisites:

-   -   A micro-column 38 defined as follows should be used. The volume        of the trapping material (e.g. silica) should be large enough to        efficiently trap (>95%) the carbon-isotope monoxide, and small        enough (<1% of the volume of a subsequent reaction chamber 50)        to allow maximal concentration of the carbon-isotope monoxide.        In the case of silica and a reaction chamber 50 volume of 200        μl, the silica volume should be 0.1-2 μl.    -   The dead volumes of the tubing and valve(s) connecting the        silica column and the reaction chamber 50 should be minimal        (<10% of the micro-autoclave volume).    -   The pressure of the carrier gas should be 3-5 times higher than        the pressure in the reaction chamber 50 before transfer (1        atm.).

In one specific preferred embodiment specifications, materials andcomponents are chosen as follows. High pressure valves from Valco®,Reodyne® or Cheminert® are used. Stainless steel tubing with o.d. 1/16”is used except for the connections to the porapac-column 8, thesilica-column 38 and the reaction chamber 50 where stainless steeltubing with o.d. 1/32″ are used in order to facilitate the translationmovement. The connections between V1, V2 and V3 should have an innerdiameter of 0.2-1 mm. The requirement is that the inner diameter shouldbe large enough not to obstruct the possibility to achieve the optimalflow of He (2-50 ml/min) through the system, and small enough not toprolong the time needed to transfer the radioactivity from theporapac-column 8 to the silica-column 38. The dead volume of theconnection between V3 and the autoclave should be minimized (<10% of theautoclave volume). The inner diameter (0.05-0.1 mm) of the connectionmust be large enough to allow optimal He flow (2-50 ml/min). The deadvolume of the connection between V4 and V5 should be less than 10% ofthe autoclave volume.

The porapac-column 8 preferably is comprised of a stainless steel tube(o.d.=⅛″, i.d.=2 mm, 1=20 mm) filled with Porapac Q® and fitted withstainless steel screens. The silica-column 38 preferably is comprised ofa stainless steel tube (o.d= 1/16”, i.d.=0.1 mm) with a cavity (d=1 mm,h=1 mm, V=0.8 μl) in the end. The cavity is filled with silica powder(100/80 mesh) of GC-stationary phase type. The end of the column isfitted against a stainless steel screen.

It should be noted that a broad range of different materials could beused in the trapping devices. If a GC-material is chosen, the criterionsshould be good retardation and good peak-shape for carbon dioxide andcarbon monoxide respectively. The latter will ensure optimal recovery ofthe radioactivity.

Below a detailed description is given of a method of producingcarbon-isotope using an exemplary system as described above.

Preparations of the system are performed by the steps 1 to 5:

-   -   1. V1 in position A, V2 in position A, V3 in position A, V4 in        position A, helium flow on with a max pressure of 5 bar. With        this setting, the helium flow goes through the porapac column,        the zinc furnace, the silica column, the reaction chamber 50 and        out through V4. The system is conditioned, the reaction chamber        50 is rid of solvent and it can be checked that helium can be        flowed through the system with at least 10 ml/min. UV lamp 91 is        turned on.    -   2. The zinc-furnace is turned on and set at 400° C.    -   3. The porapac- and silica-columns are cooled with liquid        nitrogen. At −196° C., the porapac- and silica-column        efficiently traps carbon-isotope dioxide and carbon-isotope        monoxide respectively.    -   4. V5 in position A (load). The injection loop (250 μl),        attached to V5, is loaded with the reaction mixture.    -   5. The HPLC-pump is attached to a flask with freshly distilled        THF (or other high quality solvent) and primed. V6 in position        A.

Production of carbon-isotope dioxide may be performed by the steps 6 to7:

-   -   6. Carbon-isotope dioxide is produced using the 14N(p,α)¹¹C        reaction in a target gas containing nitrogen (AGA, Nitrogen 6.0)        and 0.1% oxygen (AGA. Oxygen 4.8), bombarded with 17 MeV        protons.    -   7. The carbon-isotope dioxide is transferred to the apparatus        using nitrogen with a flow of 100 ml/min.

Synthesis of carbon-isotope may thereafter be performed by the steps 8to 16

-   -   8. V1 in position B and V2 in position B. The nitrogen flow        containing the carbon-isotope dioxide is now directed through        the porapac-column (cooled to −196° C.) and out through a waste        line. The radioactivity trapped in the porapac-column is        monitored.    -   9. When the radioactivity has peaked, V1 is changed to        position A. Now a helium flow is directed through the        porapac-column and out through the waste line. By this operation        the tubings and the porapac-column are rid of nitrogen.    -   10. V2 in position A and the porapac-column is warmed to about        50° C. The radioactivity is now released from the porapac-column        and transferred with a helium flow of 10 ml min into the        zinc-furnace where it is transformed into carbon-isotope        monoxide.    -   11. Before reaching the silica-column (cooled to −196° C.), the        gas flow passes the ascarite-column. The carbon-isotope monoxide        is now trapped on the silica-column. The radioactivity in the        silica-column is monitored and when the value has peaked, V3 is        set to position B and then V4 is set to position B.    -   12. The silica-column is heated to approximately 50° C., which        releases the carbon-isotope monoxide. V3 is set to position A        and the carbon-isotope monoxide is transferred to the reaction        chamber 50 within 15 s.    -   13. V3 is set to position B, V5 is set to position B, the        HPLC-pump is turned on (flow 7 ml/min) and V6 is set to        position B. Using the pressurized THF (or other solvent), the        reaction mixture is transferred to the reaction chamber 50. When        the HPLC-pump has reached its set pressure limit (e.g 40 Mpa),        it is automatically turned off and then V6 is set to position A.    -   14. Motor 95, magnetic stir 96 and magnet stirring bar 97 in        reaction chamber 50 are turned on.    -   15. After a sufficient reaction-time (usually 5 min), V3 is set        to position C and the content of the reaction chamber 50 is        transferred to a collection vial.    -   16. The reaction chamber 50 can be rinsed by the following        procedure: V3 is set to position B, the HPLC-pump is turned on,        V6 is set to position B and when maximal pressure is reached V6        is set to position A and V3 is set to position 3 thereby        transferring the rinse volume to the collection vial.

With the recently developed fully automated version of the reactionchamber 50 system according to the invention, the value of [¹¹C]carbonmonoxide as a precursor for ¹¹C-labelled tracers has become comparablewith [¹¹C]methyl iodide. Currently, [¹¹C]methyl iodide is the mostfrequently used ¹¹C-precursor due to ease in production and handling andsince groups suitable for labeling with [¹¹C]methyl iodide (e.g. heteroatom bound methyl groups) are common among biologically activesubstances. Carbonyl groups, that can be conveniently labeled with[¹¹C]carbon monoxide, are also common among biologically activesubstances. In many cases, due to metabolic events in vivo, a carbonylgroup may even be more advantageous than a methyl group as labelingposition. The use of [¹¹C]carbon monoxide for production of PET-tracersmay thus become an interesting complement to [¹¹C]methyl iodide.Furthermore, through the use of similar technology, this method willmost likely be applicable for synthesis of ¹³C and ¹⁴C substitutedcompounds.

The main advantage of the present invention is to overcome thelimitations of palladium or selenium mediated reaction to synthesize¹¹C-labeled amides using alkylaryl iodides and amines as precursors. Thelevels specific radioactivity are high compared with alternative methodssuch as the use of Grignard reactions for preparation of [carbonyl-¹¹C]amides. Amines used as precursors in the instant invention have aformula

, wherein R′ and R″ are independently H, linear or cyclic lower alkyl orsubstituted alkyl, aryl or substituted aryl, and may contain hydroxy,amino, alkoxy, chloro or fluoro groups. Iodides used in this inventionhave a formula RI, where R is linear or cyclic lower alkyl orsubstituted alkyl, aryl or substituted aryl, and may contain hydroxyl,alkoxy, chloro, fluoro, amino or carboxy groups. The resultant labeledamides have a formula

wherein R, R′ and R″ are defined as above. They provide valuable PETtracers in various PET studies. In an embodiment of the presentinvention, it provides kits for use as PET tracers comprising[¹¹C]-labeled amides. General reaction scheme for the synthesis oflabeled amides are as illustrated below:

EXAMPLES

The invention is further described in the following examples which arein no way intended to limit the scope of the invention.

Example 1 Precursors and Resultant Products

The following experiments illustrate the present invention. Radicalcarbonylation using submicromolar amounts of [¹¹C]carbon monoxide isperformed yielding labeled with the amides shown in Table 1 as targetcompounds.

Alkyl iodides and amines used for the labeling are shown in List. 1 andList. 2 correspondingly.

FIG. 1. Iodides used as precursors in labeling.

FIG. 2. Amines used as precursors in labeling.

The reactions were carried out in a 270 μl stainless steel reactionvessel equipped with a sapphire window. The reaction mixture containingan alkyl iodide, an amine, [¹¹C]carbon monoxide in helium and a solventwas pressurized at 35 MPa and irradiated with focused light from a Hglamp (medium pressure, 400 W) during 300-400 s. The amount of[¹¹C]carbon monoxide used in these reactions was in the range of 10⁻⁸mol (10⁻⁹ L at 35 MPa), corresponding to a partial pressure of 200 Pa.After the synthesis the crude mixture was evacuated from the reactionvessel for measurements of radioactivity and LC-analysis.

The decay corrected radiochemical yield of the target compounds wasfound to be significantly dependent on factors such as solvent polarity,nucleophilicity of the amine and structure of the organic halide(stability of the nascent free radical). When low-polar solvents (i.e.,n-hexane and cyclohexane) were used in the synthesis of 1A, theconversion of [¹¹C]carbon monoxide did not exceed 5%. We thusanticipated that more polar solvents were necessary to stabilize theacyl radicals and facilitate the acylation step enough to compete withthe

The conversion of carbon monoxide was indeed favored when the syntheseswere carried out in more polar solvents. Thus the conversion was about30% with acetone and acetonitrile and about 85% with DMF and DMSO (Table1, entry 2). However, in the case of DMF and DMSO the amounts of labeledside-products also increased (25-40% estimated by LC). When the lessreactive solvents 1-methyl-2-pyrrolidinone (NMP) and1,3-dimethyl-2-imidazolidinone (DMI) were used the amounts of labeledside-products were significantly decreased (entries 1 and 3). TABLE 1Trapping efficiency and radiochemical yields of ¹¹C-labeled amides (¹¹Clabeling position marked with *). Trapping Yield Amide Iodide AmineSolvent (%)^(a) (%)^(b) N^(d) entry

 1  A NMP DMSO DMI 81 ± 12 89 ± 9 85 ± 4  54 ± 15 42 ± 5 69 ± 5^(c ) 4 53 1 2 3

1 B NMP 89 ± 3  61 ± 8  3 4

1 D NMP 76 ± 18 44 ± 3  3 5

1 E NMP 46 ± 11 2 ± 1 3 6

2 A NMP 64 ± 11 37 ± 9  3 7

3 A NMP ethanol 10 ± 11 37 ± 7  1 ± 0 27 ± 9  3 3 8 9

4 C NMP 46 ± 13 28 ± 9  3 10 

5 A NMP 85 ± 3  57 ± 1  3 11 

6 A NMP 23 ± 2  17 ± 2  3 14 

7 A NMP 76 ± 2  43 ± 1  3 12 

9 A NMP 10 ± 3  4 ± 1 4 13 ^(a)Decay-corrected, the fraction of radioactivity left in the crudeproduct after purge with nitrogen.^(b)radiochemical yield; decay-corrected, calculated from the amount ofradioactivity in the crude product before nitrogen purge, and theradioactivity of the LC purified product.^(c)radiochemical yield; decay-corrected, calculated from analyticalHPLC.^(d)number of runs.

In choosing the solvent it is necessary to account for the reactivity ofthe amine. In DMSO, for example, aniline is comparatively as reactive(towards radicals) as the solvent resulting in low yield of the desiredproduct and in case of 2-aminopyridine no product was detected at all.Switching to NMP gives 44% radiochemical yield of amide 1D (Table 1,entry 5) and 2% of 1E (Table 1, entry 6) correspondingly.

Direct nucleophilic substitution is apparently fast enough to competewith carbonylation mechanism when iodide 3 was used as a startingmaterial. Thus only 1% of 3A was isolated with NMP as the solvent (Table1, entry 8). Acetonitrile gave the same low yield, however in n-hexanetrapping increased to 27% (yield 17%, single run), and in TMF 11% (yield8%, single run). In THF the purity of the crude product determined byHPLC was the best and reached 91%. Finally ethanol ensured the bestoverall performance (Table 1, entry 9). All these observations are inaccordance with accepted mechanism (Scheme 1).

The hydroxy functionality in aminoalcohol C did not compete with thenitrogen (Table 1, entry 10). With 2-iodoethylbenzene 4 trappingefficiency was markedly lower comparing to 1 and 2 (Table 1, entry 10).The major unlabelled byproduct in case of 4 was identified as styrene.Importance of dehydrohalogenation with other iodides was not studied.

Entry 7A present an interesting example when relative rate ofintermolecular acylation successfully competes with intramolecularnucleophilic substitution and acylation.

Phenyl iodide gave a decay corrected radiochemical yield of 4% withamine A (Table 1, entry 13).

Several organo-bromides were compared with the correspondingorgano-iodide in the labeling reactions. Generally, the conversion of[¹¹C]carbon monoxide reached relative high levels while the purity ofthe crude product was low with several side-products. For exampletrapping efficiency in preparation of 1A in DMI from cyclohexyl bromidewas 70% but LC purity of the crude product was only 18% comparing to 71%trapping efficiency and 78% purity when cyclohexyl iodide was used.

In comparison with palladium-mediated carbonylation, the correspondingfree-radical reactions showed notable dependence on the transfer rate ofcarbon monoxide between liquid and gas phases. In our previous works onpalladium and selenium-mediated carbonylations nearly quantitativeconversions of [¹¹C]carbon monoxide where obtained without stirring. Incontrast, the corresponding conversion of [¹¹C]carbon monoxide in thesynthesis of 1A was only 29±4% and increased to 85±7% with stirring.Likewise a reduction in pressure from 35 Mpa to 10 MPa resulted inthreefold decrease of the conversion.

When visible light without UV was used (a 250 W halogen lamp withUV-stop glass) no product was detected after a reaction time of 300 s.The same negative result was obtained when the Hg-lamp was used with afilter absorbing spectral range in 190-420 nm. An interestingobservation was that small amount of the labeled target compound wasobserved in experiments without irradiation. The intensity of theUV-light was also important; lower irradiation intensity gave lowerdecay corrected radiochemical yields.

Although the changes of solvent, temperature, stirring and type oforgano halide all had a pronounced effect on the decay correctedradiochemical yield the basic product pattern remained roughly the same.

The reduction of the amount of reagents used is sometimes desirable inorder to facilitate purification, reduce costs and possibly suppress theformation of side-products. The synthesis of compound 1A was used as amodel reaction to explore this point and presented as decay correctedradiochemical yield (Table 2). The amounts of side-products increasedwhen the concentration of substrates reach certain minimum level. TABLE2 Dependence of TE and radiochemical yield based on the concentration ofreagents.^(a) Concentration Concentration LC purity of 1 (mM) of A (mM)Trapping (%)^(b) (%) Yield (%)^(c) 0 65 12 0 0 1 65 36 5 2 2 65 40 16 68 65 36 39 14 15 65 83 63 52 39 65 86 75 64 77 65 91 72 66 77 3 40 5 3 87 59 10 6^(a)all reactions were performed in DMSO, 400 s.^(b)decay-corrected, the fraction of radioactivity left in the crudeproduct after purge with nitrogen.^(c)radiochemical yield; decay-corrected, calculated from analyticalHPLC.

The identities of the synthesised labelled compounds were establishedthrough analytical LC retention times. To collect more solid evidencesynthesis of compound 1A was scaled up. Reaction was performed in thesame manner and 866 μL of [¹²C]carbon monoxide was added to the reactionmixture. Amount of precursors was correspondingly increased and reactiontime prolonged to 20 min. In this case [¹¹C]carbon monoxide was used asa tracer to tack the labeled product. ¹H NMR spectrum of the isolatedcompound was identical with the spectrum of reference compound preparedby alternative synthetic route.

For compound 5A ¹³C labelling experiment was carried out. [¹³C]carbonmonoxide was added to the [¹¹C]carbon monoxide and the reaction wasperformed within the same reaction conditions except the amount of thestarting iodide and amine were accordingly scaled up and reaction timewas prolonged to 31 min in order to run the reaction closer tocompletion with respect to carbon monoxide. Calculated from carbonmonoxide decay corrected isolated yield of [¹³C]-labeled 5A was 41%based on ¹¹C activity measurements, conversion of [¹¹C]carbon monoxideto the product reached 68%. ¹³C NMR spectrum was used to assign thelabeling position. ¹H NMR spectrum showing characteristic ¹H-¹³Csplittings was used to support the identity of the labeled compound.

These experiments prove suitability of radical mediated carbonylationfor synthesis of amides labeled at carbonyl position starting from[11C]carbon monoxide, alkyl iodides and amines. This method may providean important complement to previously described palladium mediated[11C]carbon monoxide labeling strategy and makes accessible targetstructures, which will be obstructed in Grignard synthesis.

Example 2 Experimental Setup

[¹¹C]Carbon dioxide production was performed using a Scanditronix MC-17cyclotron at Uppsala IMANET. The ¹⁴N(p,α)¹¹C reaction was employed in agas target containing nitrogen (Nitrogen 6.0) and 0.1% oxygen (Oxygen4.8) which was bombarded with 17 MeV protons.

[¹¹C]Carbon monoxide was obtained by reduction of [¹¹C]carbon dioxide asdescribed in the instant application.

The syntheses with [¹¹C]carbon dioxide were performed with an automatedmodule as part of the system “Synthia 2000”.

Liquid chromatographic analysis (LC) was performed with a gradient pumpand a variable wavelength UV-detector in series with a β⁺-flow detector.The following mobile phases were used: 25 mM potassiumdihydrogenphosphate (A) and acetonitrile/H₂O: 50/7 (B3). For analyticalLC, a C₁₈, 4 μm, 250×4.6 mm ID column was used at a flow of 1.5 mL/min.For semi-preparative LC, a C₁₈, 4 μm, 250×10 mm (i.d.), column was usedat a flow of 4 mL/min. An automated synthesis system, Synthia was usedfor LC injection and fraction collection.

Radioactivity was measured in an ion chamber, Veenstra Instrumenten by,VDC-202.

A Philips HOK 4/120SE mercury lamp was used as UV radiation source.

In the analysis of the ¹¹C-labeled compounds, unlabeled referencesubstances were used for comparison in all the LC runs.

NMR spectra of synthesized compounds were recorded at 400 MHz for ¹H andat 100 MHz for ¹³C, at 25° C. Chemical shifts were referenced to TMS viathe solvent signals.

LC-MS analysis was performed using a Micromass VG Quattro withelectrospray ionization. A Beckman 126 pump, a CMA 240 autosampler wereused.

THF was distilled under nitrogen from sodium/benzophenone. DMSO waspurged with helium 5 min before use. Compound 7 was synthesized from thecorresponding bromide by Finkelstein reaction. All other startingmaterials were commercially available.

Example 3 Preparation of [11C]-labeled Amides

A capped vial (1 mL) flushed with nitrogen. The vial was charged with anamine (50 mmol) and appropriate solvent (500 μL). Organo iodide (50μmol) was added to the solution roughly 7 min before synthesis. Theresulting mixture was pressurized (35 MPa) to the micro-autoclave (200μL), pre-charged with [¹¹C]carbon monoxide at ambient temperature. Theautoclave was then irradiated with the UV-light for 400 s. Then crudereaction mixture was transferred from the autoclave to a capped vial (1mL) held under reduced pressure. After measurement of the radioactivitythe vial was purged with nitrogen and the radioactivity was measuredagain. The crude product was diluted with acetonitrile (0.55 tol mL) andinjected on the semi-preparative LC. Analytical LC and LC-MS were usedto assess the identity and radiochemical purity of the collectedfraction.

Example 4 Preparation of Amides 1A, 1B, 1D, 1E, 2A, 3A, 5A, 9A Used asReference Compounds

To the ice cooled solution of amine A, B, D, E, and triethylamine indichloromethane was added equimolar amount of corresponding acidchloride dropwise. Reaction mixture was allowed to warm up to roomtemperature and stirred for another 1 hour. Water was added and themixture was extracted with dichloromethane thrice. Solvent wasevaporated and the product was recrystalized fromdichloromethane/pentane or purified on silica using column orpreparative TLC using ethyl acetate as mobile phase.

Example 5 Preparation of Amide 7C Used as Reference Compound

Aminoalcohol C was dissolved in 2 ml of saturated sodium hydrocarbonate.3 ml of diethyl ether was added to the solution. Resulting mixture wasice cooled and equimolar amount of 3-phenyl-propionyl chloride was addeddropwise. Reaction mixture was allowed to warm up to room temperatureand stirred for another 1 hour. Water was added and the mixture wasextracted with diethyl ether thrice. Solvent was evaporated and theproduct was used without further purification.

Specific Embodiments, Citation of References

The present invention is not to be limited in scope by specificembodiments described herein. Indeed, various modifications of theinventions in addition to those described herein will become apparent tothese skilled in the art from the foregoing description and accompanyingfigures. Such modifications are intended to fall within the scope of theappended claims.

Various publications and patent applications are cited herein, thedisclosures of which are incorporated by reference in their entireties.

1. A method for labeling synthesis, comprising: (a) providing a UVreactor assembly comprising a high pressure reaction chamber, a UV lampand a concave mirror, wherein the high pressure reaction chamber havinga window facing the concave mirror, a liquid inlet and a gas inlet in abottom surface thereof, (b) providing a reagent volume to be labeled,(c) introducing a carbon-isotope monoxide enriched gas-mixture into thereaction chamber of the UV reactor assembly via the gas inlet, (d)introducing at high pressure said reagent into the reaction chamber viathe liquid inlet, (e) turning on the UV lamp and waiting for apredetermined time while the labeling synthesis occur, and (f) removingthe labeled product from the reaction chamber.
 2. A method of claim 1,wherein the carbon-isotope monoxide enriched gas-mixture is produced bya method comprising: (a) providing carbon-isotope dioxide in a suitablecarrier gas, (b) converting carbon-isotope dioxide to carbon-isotopemonoxide by introducing said gas mixture in a reactor device, (c)trapping carbon-isotope monoxide in a carbon monoxide trapping device,wherein carbon-isotope monoxide is trapped but not said carrier gas, and(d) releasing said trapped carbon-isotope monoxide from said trappingdevice in a well defined micro-plug, whereby a volume of carbon-isotopemonoxide enriched gas-mixture is achieved.
 3. A method of claim 1,wherein the carbon-isotope is ¹¹C, ¹³C, or ¹⁴C.
 4. A method of claim 1,wherein the carbon-isotope is ¹¹C.
 5. A method of claim 1, wherein thestep of introducing the reagent is performed using a pressure that isabout 80 times higher than the pressure before the introduction, inorder to maintain a pseudo one-phase system.
 6. A method of claim 1,wherein the step of waiting a predetermined time comprises stirring inthe reaction chamber to enhance the labeling synthesis.
 7. A method ofclaim 7, wherein the step of waiting a predetermined time furthercomprises adjusting the temperature of the reaction chamber so that thelabeling synthesis is enhanced.
 8. A system for labeling synthesis,comprising: (a) a UV reactor assembly comprising a high pressurereaction chamber, (b) a UV lamp, and (c) a concave mirror, wherein thehigh pressure reaction chamber having a window facing the concavemirror, a liquid inlet and a gas inlet in a bottom surface thereof,wherein the concave mirror can focus the UV light from the UV lamp, andthe focused light beam enters the window of the reaction chamber.
 9. Asystem of claim 8, further comprising a motor, a magnet, and a magneticstirring bar inside the reaction chamber.
 10. A system of claim 8,wherein the window is a sapphire window.
 11. A system of claim 8,further comprising a protective housing and a bench where the reactionchamber, UV lamp and the concave mirror can be mounted.
 12. A method forradiocarbonylation comprising reaction of carbon-isotope monoxide with acompound of formula (I) and a compound of formula (II):

to give a labeled compound of formula (II):

wherein R is linear or cyclic lower alkyl or substituted alkyl, aryl orsubstituted aryl and R′ and R″ are independently H, linear or cycliclower alkyl, or substituted alkyl, aryl or substituted aryl.
 13. Amethod of claim 12, wherein R may contain hydroxyl, alkoxy, chloro,fluoro, amino or carboxy groups.
 14. A method of claim 12, wherein R′and R″ may contain hydroxy, amino, alkoxy, chloro or fluoro groups. 15.A method of claim 12, wherein the carbon-isotope monoxide is [¹¹C]monoxide.
 16. A carbon-isotope labeled compound of formula (III),

wherein R is linear or cyclic lower alkyl or substituted alkyl, aryl orsubstituted aryl and R′ and R″ are independently H, linear or cycliclower alkyl, or substituted alkyl, aryl or substituted aryl.
 17. A kitfor PET study comprising a carbon-isotope labeled compound of formula(III),

wherein R is linear or cyclic lower alkyl or substituted alkyl, aryl orsubstituted aryl and R′ and R″ are independently H, linear or cycliclower alkyl, or substituted alkyl, aryl or substituted aryl.